Sean Leng, MD PhD, has demonstrated great promise, and unsurpassed determination, to become a leader in clinical / translational aging research. He has had advanced training in Immunology and Molecular Virology, Cytokine Research, and Internal Medicine. After a clinical and research fellowship in Geriatric Medicine and Gerontology at Johns Hopkins, he was recruited to its faculty as an Instructor in 2002 and was promoted to Assistant Professor of Medicine in 2003. He is a recipient of a short-term R21 from NIA and an internal research award at Johns Hopkins. Dr. Leng has strong mentorship from geriatrician and epidemiologist Dr. Linda Fried, Professor and Director of the Division of Geriatric Medicine and Gerontology and Center on Aging and Health, and from immunologist Dr. Noel Rose, Professor and Director of Center for Autoimmune Disease Research. They will provide him with extensive resources and a stimulating interdisciplinary environment to launch his independent academic career in translational aging research. Dr. Leng's research interest is in frailty, a common geriatric syndrome characterized by dysregulations in multiple physiologic systems and increased vulnerability to stressors, including infections, that result in severe adverse health outcomes in older adults. Based on the preliminary findings from Dr. Leng's current research, this project proposes a pilot influenza immunization study in community-dwelling frail and age-matched non-frail older adults. With this clinically well-established in vivo immune challenge, we will characterize immune dysregulation of frail older adults and translate its implications in the context of clinical import under the following specific aims: 1) Determine whether frail older adults have impaired humoral immunity measured by viral-specific antibody tilers;2) Determine whether frail older adults have impairment in vaccine-induced cell-mediated immunity (CMI) measured by number of antigen-specific CD4+ and CD8+ T cells, intracellular production of IFN-y and IL-2, and cytotoxic T lymphocyte (CTL) function. Dr. Leng will also evaluate the relationship of pre-vaccination number of specific T cell phenotype, CD8+CD28-T cells, with vaccine-induced CMI;3) To delineate whether vaccinated frail older adults have increased rate of influenza infection and its complications (pneumonia, hospitalization, and death), compared to non-frail controls, during the post-vaccination season. As our initial translational effort, this project will improve our ability to evaluate and strengthen immune function, and ultimately prevent related adverse health outcomes, including influenza infection and its devastative complications, for frail older adults. Dr. Leng's dual training in clinical geriatric medicine and basic immunology/molecular virology and cytokine research, strong mentorship, carefully designed career development program, supportive environment, and novel research plan will give him the experience and tools that he needs to develop into a highly successful, independent physician/geriatrician-scientist.